The domain within your query sequence starts at position 670 and ends at position 748; the E-value for the PDZ domain shown below is 3.09e-15.

PDZ

Domain present in PSD-95, Dlg, and ZO-1/2.

SMART accession number:

SM00228

Description:

Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

PDZ domains (also known as Discs-large homologous regions (DHR) or GLGF)) are found in diverse signalling proteins in bacteria, yeasts, plants, insects and vertebrates [(PUBMED:9041651), (PUBMED:9204764)]. PDZ domains can occur in one or multiple copies and are nearly always found in cytoplasmic proteins. They bind either the carboxyl-terminal sequences of proteins or internal peptide sequences [(PUBMED:9204764)]. In most cases, interaction between a PDZ domain and its target is constitutive, with a binding affinity of 1 to 10 microns. However, agonist-dependent activation of cell surface receptors is sometimes required to promote interaction with a PDZ protein. PDZ domain proteins are frequently associated with the plasma membrane, a compartment where high concentrations of phosphatidylinositol 4,5-bisphosphate (PIP2) are found. Direct interaction between PIP2 and a subset of class II PDZ domains (syntenin, CASK, Tiam-1) has been demonstrated.

PDZ domains consist of 80 to 90 amino acids comprising six beta-strands (beta-A to beta-F) and two alpha-helices, A and B, compactly arranged in a globular structure. Peptide binding of the ligand takes place in an elongated surface groove as an anti-parallel beta-strand interacts with the beta-B strand and the B helix. The structure of PDZ domains allows binding to a free carboxylate group at the end of a peptide through a carboxylate-binding loop between the beta-A and beta-B strands.

Tail-specific protease (Tsp) is a periplasmic enzyme that selectively degrades proteins bearing a nonpolar C-terminus. Its substrate specificity suggests that Tsp may contain a substrate recognition domain, which selectively binds to the nonpolar C-termini of substrate proteins, separate from its catalytic site. In this work, we show that substrate recognition of Tsp is mediated by a PDZ domain, a small protein module that promotes protein-protein interactions by binding to internal or C-terminal sequences of their partner proteins. Partial proteolysis by V8 protease at a single peptide bond immediately N-terminal to the PDZ domain resulted in two distinct and relatively stable fragments and complete loss of catalytic activity. Photoaffinity labeling with a fluorescent nonpolar peptide caused the covalent attachment of the peptide to a single site on the Tsp protein. Systematic deletion mutagenesis of Tsp localized the binding site to amino acids 206-307, a region that completely encompasses the putative PDZ domain (217-301). The isolated PDZ domain (amino acids 206-334) is capable of folding into a well-behaved structure and binds to a nonpolar peptide with a dissociation constant (K(D)) of 1.9 microM, similar to that of the intact Tsp protein. Site-directed mutagenesis of a surface residue at the peptide binding site of the PDZ domain, valine 229, to Glu or Gln resulted in an increase in the K(M) value but had no effect on the k(cat) value. The use of a separate substrate recognition domain such as a PDZ domain may be a general mechanism for achieving selective protein degradation.

Protein tyrosine binding (PTB) and 'post synaptic density disc-large zo-1' (PDZ) domains bind to short peptidic ligands by augmentation of one of the domain's beta sheets and other recognition mechanisms. The two domain classes have a superficial resemblance to each other, even though no sequential homology exists. The structural bases of the interactions are well understood for the few domains now experimentally determined, and ligand-target pairs can probably be identified in favorable cases by analogy with the known domains. For both PTB and PDZ classes, functional activities are still not fully defined: it is possible that these domain classes, along with pleckstrin homology domains, have multiple roles.

Extracellular signals are normally presented to one surface of epithelial cells and to one end of neurons, and so neuronal and epithelial cell signaling is inherently polarized. Another aspect of signaling polarity is that receptors are often asymmetrically distributed on the surfaces of polarized cells. Recent evidence from studies of Caenorhabditis elegans shows that signaling polarity plays an important role in development. The underlying mesoderm induces the overlying ectoderm to form the vulva, and asymmetric distribution of the signal receptor on the basolateral surface of the epithelium is crucial for this signaling. In neurons, the localization of neurotransmitter receptors and ion channels at synapses allows neurons to be exquisitely sensitive to synaptic inputs. Exciting recent reports suggest that receptor localization to neuronal synapses and the basolateral membrane domains of epithelia may involve a common molecular mechanism involving localization by PDZ-containing proteins.

The complex anatomy of neurons demands a high degree of functional organization. Therefore, membrane receptors and ion channels are often localized to selected subcellular sites and coupled to specific signal transduction machineries. PDZ domains have come into focus as protein interaction modules that mediate the binding of a class of submembraneous proteins to membrane receptors and ion channels and thus subserve these organizational aspects. The structures of two PDZ domains have been resolved, which has led to a structural understanding of the specificity of interactions of various PDZ domains with their respective partners. The functional implications of PDZ domain interactions are now being addressed in vitro and in vivo.

Several dozen signaling proteins are now known to contain 80-100 residue repeats, called PDZ (or DHR or GLGF) domains, several of which interact with the C-terminal tetrapeptide motifs X-Ser/Thr-X-Val-COO- of ion channels and/or receptors. PDZ domains have previously been noted only in mammals, flies, and worms, suggesting that the primordial PDZ domain arose relatively late in eukaryotic evolution. Here, techniques of sequence analysis-including local alignment, profile, and motif database searches-indicate that PDZ domain homologues are present in yeast, plants, and bacteria. It is suggested that two PDZ domains occur in bacterial high-temperature requirement A (htrA) and one in tail-specific protease (tsp) homologues, and that a yeast htrA homologue contains four PDZ domains. Sequence comparisons suggest that the spread of PDZ domains in these diverse organisms may have occurred via horizontal gene transfer. The known affinity of Escherichia coli tsp for C-terminal polypeptides is proposed to be mediated by its PDZ-like domain, in a similar manner to the binding of C-terminal polypeptides by animal PDZ domains.

PDZ (also called DHR or GLGF) domains are found in diverse membrane-associated proteins including members of the MAGUK family of guanylate kinase homologues, several protein phosphatases and kinases, neuronal nitric oxide synthase, and several dystrophin-associated proteins, collectively known as syntrophins. Many PDZ domain-containing proteins appear to be localised to highly specialised submembranous sites, suggesting their participation in cellular junction formation, receptor or channel clustering, and intracellular signalling events. PDZ domains of several MAGUKs interact with the C-terminal polypeptides of a subset of NMDA receptor subunits and/or with Shaker-type K+ channels. Other PDZ domains have been shown to bind similar ligands of other transmembrane receptors. Recently, the crystal structures of PDZ domains, with and without ligand, have been determined. These demonstrate the mode of ligand-binding and the structural bases for sequence conservation among diverse PDZ domains.

InaD, a Drosophila photoreceptor scaffolding protein, assembles multiple signal-transducing proteins at the membrane via its five PDZ domains, enhancing speed and efficiency of vision. Extensive conservation of PDZ domains suggests that these motifs have a general role in organizing diverse signaling complexes.

The oriented peptide library technique was used to investigate the peptide-binding specificities of nine PDZ domains. Each PDZ domain selected peptides with hydrophobic residues at the carboxyl terminus. Individual PDZ domains selected unique optimal motifs defined primarily by the carboxyl terminal three to seven residues of the peptides. One family of PDZ domains, including those of the Discs Large protein, selected peptides with the consensus motif Glu-(Ser/Thr)-Xxx-(Val/Ile) (where Xxx represents any amino acid) at the carboxyl terminus. In contrast, another family of PDZ domains, including those of LIN-2, p55, and Tiam-1, selected peptides with hydrophobic or aromatic side chains at the carboxyl terminal three residues. On the basis of crystal structures of the PSD-95-3 PDZ domain, the specificities observed with the peptide library can be rationalized.

Modular PDZ domains, found in many cell junction-associated proteins, mediate the clustering of membrane ion channels by binding to their C-terminus. The X-ray crystallographic structures of the third PDZ domain from the synaptic protein PSD-95 in complex with and in the absence of its peptide ligand have been determined at 1.8 angstroms and 2.3 angstroms resolution, respectively. The structures reveal that a four-residue C-terminal stretch (X-Thr/Ser-X-Val-COO(-)) engages the PDZ domain through antiparallel main chain interactions with a beta sheet of the domain. Recognition of the terminal carboxylate group of the peptide is conferred by a cradle of main chain amides provided by a Gly-Leu-Gly-Phe loop as well as by an arginine side chain. Specific side chain interactions and a prominent hydrophobic pocket explain the selective recognition of the C-terminal consensus sequence.

PDZ domains can dimerize or bind to the carboxyl termini of unrelated proteins. Crystallographic studies demonstrate the structural basis for these interactions, which contribute to the ability of PDZ domains to create networks associated with the plasma membrane.

PDZ domains (also known as DHR domains or GLGF repeats) are approximately 90-residue repeats found in a number of proteins implicated in ion-channel and receptor clustering, and the linking of receptors to effector enzymes. PDZ domains are protein-recognition modules; some recognize proteins containing the consensus carboxy-terminal tripeptide motif S/TXV with high specificity. Other PDZ domains form homotypic dimers: the PDZ domain of the neuronal enzyme nitric oxide synthase binds to the PDZ domain of PSD-95, an interaction that has been implicated in its synaptic association. Here we report the crystal structure of the third PDZ domain of the human homologue of the Drosophila discs-large tumour-suppressor gene product, DlgA. It consists of a five-stranded antiparallel beta-barrel flanked by three alpha-helices. A groove runs over the surface of the domain, ending in a conserved hydrophobic pocket and a buried arginine; we suggest that this is the binding site for the C-terminal peptide.

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PDZ domain which could be assigned to a KEGG orthologous group, and not all proteins containing PDZ domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.